Q4 LONG ANSWER 10M ★ High-yield

Classify the cytotoxic anticancer drugs. Describe the alkylating agents, antimetabolites and natural products with their distinctive toxicities.

Pharmacology · 2nd Professional — Para-Clinical

Alkylating Agents

Alkylating agents transfer alkyl groups to DNA, chiefly to the N7 position of guanine, causing cross-linking, strand breaks and miscoding. They are cell cycle non-specific.

Class	Drugs	Distinctive toxicity and use
Nitrogen mustards	Cyclophosphamide, ifosfamide, chlorambucil, melphalan, bendamustine	Cyclophosphamide is a prodrug activated by hepatic CYP; its metabolite acrolein causes haemorrhagic cystitis, prevented by hydration and mesna. Also causes SIADH. Widely used in lymphoma, breast cancer, and as an immunosuppressant in vasculitis and lupus nephritis
Nitrosoureas	Carmustine, lomustine	Highly lipid-soluble, so they cross the blood–brain barrier — used in brain tumours; cause delayed and prolonged myelosuppression
Alkyl sulphonate	Busulfan	Selective for myeloid cells; pulmonary fibrosis ("busulfan lung"), skin hyperpigmentation, seizures; used in transplant conditioning
Triazenes	Dacarbazine, temozolomide	Temozolomide crosses into the CNS and is standard in glioblastoma
Platinum compounds	Cisplatin, carboplatin, oxaliplatin	Act like alkylating agents by forming DNA cross-links. Cisplatin is nephrotoxic, ototoxic, neurotoxic and intensely emetogenic; carboplatin is chiefly myelosuppressive; oxaliplatin causes cold-induced peripheral neuropathy

CLINICAL PEARL

Mesna prevents haemorrhagic cystitis by acting only where the toxin is. Cyclophosphamide releases acrolein, which concentrates in the bladder. Mesna is a thiol that is excreted into urine and binds acrolein there, inactivating it in the bladder without touching the anticancer effect elsewhere. It is a good example of protecting a specific normal tissue rather than reducing the dose.

Antimetabolites

Drug	Mechanism	Uses and toxicity
Methotrexate	Inhibits dihydrofolate reductase, blocking thymidylate and purine synthesis — S phase specific	Leukaemia, lymphoma, choriocarcinoma, osteosarcoma; and at low dose in rheumatoid arthritis and psoriasis. Causes mucositis, myelosuppression, hepatotoxicity, pneumonitis and nephrotoxicity. Folinic acid "rescue" after high-dose therapy bypasses the blocked enzyme and spares normal cells
5-fluorouracil, capecitabine	Its metabolite inhibits thymidylate synthase	Colorectal, breast, gastric and head and neck cancer. Causes mucositis, diarrhoea, myelosuppression and hand-foot syndrome. Severe toxicity occurs in DPD-deficient patients
Cytarabine (Ara-C)	A pyrimidine analogue incorporated into DNA, terminating the chain	Acute myeloid leukaemia; causes myelosuppression, mucositis and, at high dose, cerebellar toxicity and conjunctivitis
6-mercaptopurine, azathioprine, 6-thioguanine	Purine analogues	Maintenance in acute lymphoblastic leukaemia; immunosuppression. Inactivated by xanthine oxidase, so the dose must be cut to about a quarter if allopurinol is given. TPMT deficiency causes severe myelosuppression
Gemcitabine	Nucleoside analogue	Pancreatic, lung and bladder cancer
Hydroxyurea	Inhibits ribonucleotide reductase	Chronic myeloid leukaemia and myeloproliferative disease; also raises fetal haemoglobin in sickle cell disease

Natural Products

Group	Drugs	Mechanism and toxicity
Vinca alkaloids	Vincristine, vinblastine, vinorelbine	Bind tubulin and prevent microtubule assembly, arresting cells in metaphase. Vincristine causes peripheral neuropathy (dose-limiting) with little myelosuppression; vinblastine is the reverse. Fatal if given intrathecally
Taxanes	Paclitaxel, docetaxel	The opposite mechanism — they stabilise microtubules and prevent disassembly, which is equally fatal to mitosis. Cause hypersensitivity (requiring premedication), neuropathy, myelosuppression and alopecia
Topoisomerase II inhibitors	Etoposide; anthracyclines	Cause DNA strand breaks; etoposide is associated with secondary leukaemia
Topoisomerase I inhibitors	Irinotecan, topotecan	Irinotecan causes severe early (cholinergic, treated with atropine) and late diarrhoea
Anthracyclines	Doxorubicin, daunorubicin, epirubicin	Intercalate DNA, inhibit topoisomerase II and generate free radicals. Dose-related cardiomyopathy is the limiting toxicity — the cumulative dose must be tracked, and dexrazoxane is protective. Potent vesicants
Bleomycin	Causes free radical DNA strand breaks	Almost NO myelosuppression, which is why it combines well; but causes dose-related pulmonary fibrosis, worsened by oxygen therapy — anaesthetists must be told
Asparaginase	Depletes asparagine, which leukaemic cells cannot synthesise	Acute lymphoblastic leukaemia; causes hypersensitivity, pancreatitis, hyperglycaemia and thrombosis

Organ-specific Toxicities to Remember

Toxicity	Drug	Prevention or monitoring
Haemorrhagic cystitis	Cyclophosphamide, ifosfamide	Hydration and mesna
Cardiomyopathy	Anthracyclines; trastuzumab	Cumulative dose limit; echocardiography; dexrazoxane
Pulmonary fibrosis	Bleomycin, busulfan, methotrexate	Cumulative dose; avoid high inspired oxygen
Nephrotoxicity	Cisplatin, methotrexate	Vigorous hydration; urinary alkalinisation for methotrexate
Peripheral neuropathy	Vincristine, cisplatin, oxaliplatin, taxanes	Dose reduction; there is no effective prophylaxis
Ototoxicity	Cisplatin	Audiometry
Secondary leukaemia	Alkylating agents, etoposide	Long-term follow-up

Cell Cycle Specificity of the Cytotoxics

Category	Drugs	Practical consequence
Cell cycle specific — S phase	Methotrexate, 5-fluorouracil, cytarabine, 6-mercaptopurine, hydroxyurea	Schedule-dependent — prolonged infusion or divided doses catch more cells as they enter S phase; a single large dose is wasteful
Cell cycle specific — M phase	Vincristine, vinblastine, paclitaxel, docetaxel	Also schedule-dependent
Cell cycle specific — G2	Bleomycin, etoposide	Schedule-dependent
Cell cycle non-specific	Alkylating agents, platinum compounds, anthracyclines, nitrosoureas, dacarbazine	Dose-dependent — larger intermittent doses give greater kill; they also reach cells in G0, so they work in slowly growing tumours where the specific agents do not

This distinction dictates the schedule as much as the choice — giving a schedule-dependent drug as a single bolus, or a dose-dependent one as a low continuous infusion, wastes its particular advantage

Applied Aspects

Track the cumulative anthracycline dose across a patient's whole treatment history, including previous regimens; cardiomyopathy relates to lifetime exposure and may appear years later
Tell the anaesthetist about previous bleomycin; high inspired oxygen can precipitate fatal pulmonary fibrosis long after treatment has finished
Check TPMT before thiopurines and DPD before fluorouracil where available; both predict severe and occasionally fatal toxicity
Never combine allopurinol with a full dose of azathioprine or mercaptopurine
Hydrate before and after cisplatin, monitor magnesium (which is invariably lost), and use aggressive antiemetic prophylaxis, since it is among the most emetogenic drugs in use
Handle cytotoxic drugs with proper precautions; preparation in a biological safety cabinet protects staff, and spill procedures must be known
Give allopurinol and hydration before treating a bulky lymphoma or leukaemia, since tumour lysis syndrome is far easier to prevent than to treat
Cyclophosphamide has an important non-oncological role in lupus nephritis and vasculitis, where the same toxicities apply and mesna and hydration are equally necessary
Anticipate the nadir — counsel the patient about the days when they are most vulnerable to infection, and arrange blood counts to coincide
Bleomycin causes almost no myelosuppression, which is precisely why it combines so well with marrow-toxic drugs; its limiting toxicity lies elsewhere entirely
Vinca alkaloids and taxanes act on the same structure in opposite directions — one prevents assembly and the other prevents disassembly — and both arrest mitosis, which is a useful reminder that disrupting a dynamic process in either direction is equally lethal to it
Check for a history of previous chest radiotherapy before an anthracycline, since the cardiac risks are additive
Ifosfamide causes an encephalopathy distinct from that of cyclophosphamide, treated with methylene blue, and it must not be confused with cerebral metastases

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